Alternative titles; symbols
HGNC Approved Gene Symbol: UBE2D3
Cytogenetic location: 4q24 Genomic coordinates (GRCh38): 4:102,794,383-102,868,895 (from NCBI)
See UBE2D1 (602961) for general information about ubiquitination and the UBC4/5 subfamily of E2 enzymes.
By PCR using oligonucleotides based on UBCH5B (UBE2D2; 602962), Jensen et al. (1995) identified a human peripheral blood lymphocyte cDNA encoding UBCH5C, or UBE2D3. The predicted 147-amino acid UBCH5C and UBCH5B proteins differ by only 4 amino acids, with 3 of the differences conservative changes; the nucleotide sequences of their cDNAs are 87% identical within the coding region and 23% conserved within the 3-prime untranslated region. The UBCH5C protein has 94% sequence identity with the Drosophila UbcD1 protein, 92% identity with C. elegans ubc2, 88% identity with human UBCH5A (UBE2D1), and 79% identity with S. cerevisiae UBC4 and UBC5, and Arabidopsis thaliana UBC8 and UBC9. Recombinant UBCH5C expressed in E. coli had a molecular mass of 16 kD by SDS-PAGE. Quantitative PCR showed that UBCH5C was expressed in all human tissues examined and at higher levels than UBCH5A and UBCH5B.
Jensen et al. (1995) demonstrated that UBCH5C could conjugate ubiquitin to target proteins in an E6AP (UBE3A; 601623)-dependent manner.
All-trans retinoic acid (RA) is used in differentiation therapy to achieve remission of acute promyelocytic leukemia (APL) because it causes APL cell cycle arrest and differentiation. Using a short hairpin RNA screen, Hattori et al. (2007) identified UBE2D3 among 26 proteins that were essential for RA-induced differentiation and growth arrest in NB4 human promyelocytic cells. UBE2D3 was upregulated following RA treatment of NB4 cells. UBE2D3 physically associated with cyclin D1 (CCND1; 168461) and mediated RA-induced cyclin D1 degradation. Knockdown of UBE2D3 by RNA interference blocked RA-induced cyclin D1 degradation and cell cycle arrest. Hattori et al. (2007) concluded that ubiquitin-mediated proteolysis is involved in RA-induced cell cycle arrest.
Shembade et al. (2010) showed that A20 (191163) inhibits the E3 ligase activities of TRAF6 (602355), TRAF2 (601895), and cIAP1 (601712) by antagonizing interactions with E2 ubiquitin-conjugating enzymes UBC13 (603679) and UBCH5C. A20, together with the regulatory molecule TAX1BP1 (605326), interacted with UBC13 and UBCH5C and triggered their ubiquitination and proteasome-dependent degradation. These findings suggested a mechanism of A20 action in the inhibition of inflammatory signaling pathways.
Okiyoneda et al. (2010) identified the components of the peripheral protein quality control network that removes unfolded CFTR containing the F508del mutation (602421.0001) from the plasma membrane. Based on their results and proteostatic mechanisms at different subcellular locations, Okiyoneda et al. (2010) proposed a model in which the recognition of unfolded cytoplasmic regions of CFTR is mediated by HSC70 (600816) in concert with DNAJA1 (602837) and possibly by the HSP90 machinery (140571). Prolonged interaction with the chaperone-cochaperone complex recruits CHIP (607207)-UBCH5C and leads to ubiquitination of conformationally damaged CFTR. This ubiquitination is probably influenced by other E3 ligases and deubiquitinating enzyme activities, culminating in accelerated endocytosis and lysosomal delivery mediated by Ub-binding clathrin adaptors and the endosomal sorting complex required for transport (ESCRT) machinery, respectively. In an accompanying perspective, Hutt and Balch (2010) commented that the 'yin-yang' balance maintained by the proteostasis network is critical for normal cellular, tissue, and organismal physiology.
Crystal Structure
McGinty et al. (2014) crystallized the Polycomb repressive complex-1 (PRC1) ubiquitylation module, an E2-E3 enzyme complex composed of UBCH5C and the minimal RING1B (608985)-BMI1 (164831) ring heterodimer, bound to its nucleosome core particle substrate. The authors solved the structure at 3.3-angstrom resolution. The structure shows how a chromatin enzyme achieves substrate specificity by interacting with several nucleosome surfaces spatially distinct from the site of catalysis. McGinty et al. (2014) concluded that the structure revealed an unexpected role for the ubiquitin E2 enzyme in substrate recognition, and provides insight into how a related histone H2A E3 ligase, BRCA1 (113705), interacts with and ubiquitylates the nucleosome.
Hattori, H., Zhang, X., Jia, Y., Subramanian, K. K., Jo, H., Loison, F., Newburger, P. E., Luo, H. R. RNAi screen identifies UBE2D3 as a mediator of all-trans retinoic acid-induced cell growth arrest in human acute promyelocytic NB4 cells. Blood 110: 640-650, 2007. [PubMed: 17420285] [Full Text: https://doi.org/10.1182/blood-2006-11-059048]
Hutt, D., Balch, W. E. The proteome in balance. Science 329: 766-767, 2010. [PubMed: 20705837] [Full Text: https://doi.org/10.1126/science.1194160]
Jensen, J. P., Bates, P. W., Yang, M., Vierstra, R. A., Weissman, A. M. Identification of a family of closely related human ubiquitin conjugating enzymes. J. Biol. Chem. 270: 30408-30414, 1995. [PubMed: 8530467] [Full Text: https://doi.org/10.1074/jbc.270.51.30408]
McGinty, R. K., Henrici, R. C., Tan, S. Crystal structure of the PRC1 ubiquitylation module bound to the nucleosome. Nature 514: 591-596, 2014. [PubMed: 25355358] [Full Text: https://doi.org/10.1038/nature13890]
Okiyoneda, T., Barriere, H., Bagdany, M., Rabeh, W. M., Du, K., Hohfeld, J., Young, J. C., Lukacs, G. L. Peripheral protein quality control removes unfolded CFTR from the plasma membrane. Science 329: 805-810, 2010. [PubMed: 20595578] [Full Text: https://doi.org/10.1126/science.1191542]
Shembade, N., Ma, A., Harhaj, E. W. Inhibition of NF-kappa-B signaling by A20 through disruption of ubiquitin enzyme complexes. Science 327: 1135-1139, 2010. [PubMed: 20185725] [Full Text: https://doi.org/10.1126/science.1182364]